Combined optokinetic stimulation and cueing-assisted reading therapy to treat hemispatial neglect: A randomized controlled crossover trial.

BACKGROUND: Hemispatial neglect is a disabling cognitive disorder following stroke and effective therapies are required. OBJECTIVES: To evaluate the effects of combined optokinetic stimulation (OKS) and cueing-assisted reading therapy (READ) on the remission of hemispatial neglect following stroke. METHODS: Randomized, controlled, two-period, crossover trial conducted at a German neurorehabilitation center. Twenty participants with left neglect following right hemispheric stroke (mean age 66 years (SD 11), mean time since stroke 50 days (SD 33)) finished the trial (12 received OKSREAD first, 8 CONTROL first). The intervention consisted of 15 daily sessions of OKS (20 min) and text reading assisted by a therapist providing cues (20 min). The control treatment was a same-number, same-length neuropsychological treatment not targeting visuospatial attention. Primary outcomes were the change in performance of a customized neuropsychological test battery for neglect (0% worst - 100% best) and a test of neglect-related functional disability (Catherine Bergego Scale, 0 no impairment - 30 severest impairment), assessed before and after each treatment period. Secondary outcomes were performance in the 6 single tests composing the battery (e.g., omissions in text reading, center of cancellation in the Bells test, spatial bias of fixations when freely viewing photographs) and a clinical test of anosognosia. RESULTS: Overall performance in the neglect test battery improved slightly more after OKSREAD than after CONTROL (d=6%; p=0.002). The remission of neglect-related functional disability did not differ between treatments (d=-2; p=0.291). Ipsilesional fixation bias during free viewing was the only secondary outcome that was improved by OKSREAD as compared to CONTROL (d= -2.8°; p=0.005). CONCLUSION: At the applied intensity, the combined OKSREAD intervention slightly attenuated the ipsilesional attention bias in persons with neglect, but it did not improve neglect-related functional disability, anosognosia, or other neglect symptoms to a clinically meaningful degree. CLINICAL TRIAL REGISTRATION: URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT04273620.

Discharging the medial knee compartment: comparison of pressure distribution and kinematic shifting after implantation of an extra-capsular absorber system (ATLAS) and open-wedge high tibial osteotomy-a biomechanical in vitro analysis.

PURPOSE: Young and active patients suffering early degenerative changes of the medial compartment with an underlying straight-leg axis do face a therapeutical gap as unloading of the medial compartment cannot be achieved by high tibial osteotomy. Extracapsular absorbing implants were developed to close this existing therapeutical gap. Purpose of the present cadaveric biomechanical study was to compare the unloading effect of the knee joint after implantation of an extra-articular absorber system (ATLAS) in comparison to open-wedge high tibial osteotomy (OW-HTO) under physiological conditions. The hypothesis of the study was that implantation of an extra-capsular absorber results in an unloading effect comparable to the one achievable with OW-HTO. METHODS: Eight fresh-frozen cadaveric knees were tested under isokinetic flexion-extension motions and physiological loading using a biomechanical knee simulator. Tibiofemoral area contact and peak contact pressures were measured using pressure-sensitive film in the untreated medial compartment. The tibiofemoral superior-inferior, latero-medial translation and varus/valgus rotation were measured with a 3D tracking system Polaris. Pressures and kinematics changes were measured after native testing, ATLAS System implantation and OW-HTO (5° and 10° correction angles) performed with an angular stable internal fixator (TomoFix). RESULTS: The absorber device decreased the pressure in the medial compartment near full extension moments. Implantation of the ATLAS absorbing system according to the manufacturers' instruction did not result in a significant unloading effect. Deviating from the surgery manual provided by the manufacturer the implantation of a larger spring size while applying varus stress before releasing the absorber resulted in a significant pressure diminution. Contact pressure decreased significantly Δ0.20 ± 0.04 MPa p = 0.044. Performing the OW-HTO in 5° correction angle resulted in significant decreased contact pressure (Δ0.25 ± 0.10 MPa, p = 0.0036) and peak contact pressure (Δ0.39 ± 0.38 MPa, p = 0.029) compared with the native test cycle. With a 10° correction angle, OW-HTO significantly decreased area contact pressure by Δ0.32 ± 0.09 MPa, p = 0.006 and peak contact pressure by Δ0.48 ± 0.12 MPa, p = 0.0654 compared to OW-HTO 5°. Surgical treatment did not result in kinematic changes regarding the superior-inferior translation of the medial joint section. A significant difference was observed for the translation towards the lateral compartment for the ATLAS system Δ1.31 ± 0.54 MPa p = 0.022 and the osteotomy Δ3.51 ± 0.92 MPa p = 0.001. Furthermore, significant shifting varus to valgus rotation of the treated knee joint was verified for HTO 5° about Δ2.97-3.69° and for HTO 10° Δ4.11-5.23° (pHTO 5 = 0.0012; pHTO 10 = 0.0007) over the entire extension cycle. CONCLUSION: OW-HTO results in a significant unloading of the medial compartment. Implantation of an extra-capsular absorbing device did not result in a significant unloading until the implantation technique was applied against the manufacturer's recommendation. While the clinical difficulty for young and active patients with straight-leg axis and early degenerative changes of the medial compartment persists further biomechanical research to develop sufficient unloading devices is required.

Gaze-contingent display technology can help to reduce the ipsilesional attention bias in hemispatial neglect following stroke.

BACKGROUND: Hemispatial neglect results from unilateral brain damage and represents a disabling unawareness for objects in the hemispace opposite the brain lesion (contralesional). The patients' attentional bias for ipsilesional hemispace represents a hallmark of neglect, which results from an imbalanced attentional priority map in the brain. The aim of this study was to investigate whether gaze-contingent display (GCD) technology, reducing the visual salience of objects in ipsilesional hemispace, is able to rebalance this map and increase awareness and exploration of objects in the neglected contralesional hemispace. METHODS: Using remote eye-tracking, we recorded gaze positions in 19 patients with left hemispatial neglect following right-hemisphere stroke and 22 healthy control subjects, while they were watching static naturalistic scenes. There were two task conditions, free viewing (FV) or goal-directed visual search (VS), and four modification conditions including the unmodified original picture, a purely static modification and two differently strong modifications with an additional gaze-contingent mask (GC-LOW, GC-HIGH), that continuously reduced color saturation and contrast of objects in the right hemispace. RESULTS: The patients' median gaze position (Center of Fixation) in the original pictures was markedly deviated to the right in both tasks (FV: 6.8° ± 0.8; VS: 5.5° ± 0.7), reflecting the neglect-typical ipsilesional attention bias. GC modification significantly reduced this bias in FV (GC-HIGH: d = - 3.2 ± 0.4°; p < 0.001). Furthermore, in FV and VS, GC modification increased the likelihood to start visual exploration in the (neglected) left hemifield by about 20%. This alleviation of the ipsilesional fixation bias was not associated with an improvement in detecting left-side targets, in contrast, the GC mask even decreased and slowed the detection of right-side targets. Subjectively, patients found the intervention pleasant and most of the patients did not notice any modification. CONCLUSIONS: GCD technology can be used to positively influence visual exploration patterns in patients with hemispatial neglect. Despite an alleviation of the neglect-related ipsilesional fixation bias, a concomitant functional benefit (improved detection of contralesional targets) was not achieved. Future studies may investigate individualized GCD-based modifications as augmented reality applications during the activities of daily living.

Two-component carnitine monooxygenase from Escherichia coli: functional characterization, inhibition and mutagenesis of the molecular interface.

Gut microbial production of trimethylamine (TMA) from l-carnitine is directly linked to cardiovascular disease. TMA formation is facilitated by carnitine monooxygenase, which was proposed as a target for the development of new cardioprotective compounds. Therefore, the molecular understanding of the two-component Rieske-type enzyme from Escherichia coli was intended. The redox cofactors of the reductase YeaX (FMN, plant-type [2Fe-2S] cluster) and of the oxygenase YeaW (Rieske-type [2Fe-2S] and mononuclear [Fe] center) were identified. Compounds meldonium and the garlic-derived molecule allicin were recently shown to suppress microbiota-dependent TMA formation. Based on two independent carnitine monooxygenase activity assays, enzyme inhibition by meldonium or allicin was demonstrated. Subsequently, the molecular interplay of the reductase YeaX and the oxygenase YeaW was addressed. Chimeric carnitine monooxygenase activity was efficiently reconstituted by combining YeaX (or YeaW) with the orthologous oxygenase CntA (or reductase CntB) from Acinetobacter baumannii. Partial conservation of the reductase/oxygenase docking interface was concluded. A structure guided mutagenesis approach was used to further investigate the interaction and electron transfer between YeaX and YeaW. Based on AlphaFold structure predictions, a total of 28 site-directed variants of YeaX and YeaW were kinetically analyzed. Functional relevance of YeaX residues Arg271, Lys313 and Asp320 was concluded. Concerning YeaW, a docking surface centered around residues Arg83, Lys104 and Lys117 was hypothesized. The presented results might contribute to the development of TMA-lowering strategies that could reduce the risk for cardiovascular disease.

Patellofemoral cartilage defects are acceptable in patients undergoing high tibial osteotomy for medial osteoarthritis of the knee.

BACKGROUND: Patients suffering cartilage defects of the medial compartment with underlying varus deformity do benefit from high tibial osteotomy (HTO) even in the long term. Nonetheless, kinematic and geometric changes especially in the patellofemoral joint have been described. Purpose of the present study was to evaluate the influence of patellofemoral cartilage defects detected during the diagnostic arthroscopy and their influence on HTO's postoperative outcome. METHODS: Ninety patients with a mean follow-up of 10.08 ± 2.33 years after surgery were included. Patients were divided into four groups according to their cartilage status in the patellofemoral joint (A = no defects, B = isolated lesions of the patella, C = isolated lesions of the trochlea, D = kissing lesions). Functional outcome was evaluated before surgery and about ten years thereafter by relying on the IKDC, Lysholm, and KOOS scores. Radiological parameters were assessed pre- and six weeks postoperatively. RESULTS: In groups A to D, the HTO led to significant patellar distalisation in the sagittal view, with the mean indices remaining at or above the limit to a patella baja. All patients in all groups profited significantly from HTO (higher Lysholm score, lower VAS p < 0.001), patients in group D had the lowest outcome scores. Patella height negatively influenced outcome scores in group C (Blackburne-Peel-Index-VAS p = 0.033) and D (Caton-Deschamps-Index-Tegner p = 0.018), a larger valgus correction was associated with lower outcome scores in group D (Lysholm p = 0.044, KOOSpain 0.028, KOOSQOL p = 0.004). CONCLUSION: Long-term results of HTO for varus medial compartment osteoarthritis remain good to excellent even in the presence of patellofemoral defects. Overcorrection should be avoided. Distal biplanar HTO should be considered for patients presenting trochlear or kissing lesions of the patellofemoral joint. TRIAL REGISTRATION: DRKS00015733 in the German Registry of Clinical Studies.

10-Year Survival Rates After High Tibial Osteotomy Using Angular Stable Internal Plate Fixation: Case Series With Subgroup Analysis of Outcomes After Combined Autologous Chondrocyte Implantation and High Tibial Osteotomy.

BACKGROUND: Good-to-excellent midterm results after high tibial osteotomy (HTO) to treat medial compartment cartilage defects or osteoarthritis (OA) have been published, but little is known about long-term survival rates in terms of conversion to total knee arthroplasty (TKA) using angular stable internal plate fixation. PURPOSE: To determine TKA-free survival rates and functional and radiological outcomes at 10 years after HTO. A subgroup analysis of patients who underwent combined HTO and autologous cartilage implantation (ACI) was also performed. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Included were 125 patients with a mean follow-up of 9.90 ± 2.25 years; 90 patients underwent HTO for medial OA, and 35 patients underwent ACI and HTO for medial focal cartilage defects. Functional outcome measures included visual analog scale (VAS) for pain, Lysholm, International Knee Documentation Committee (IKDC), and Knee injury and Osteoarthritis Outcome Score (KOOS) subscales and KOOS4 (average of 4 KOOS subscales: Pain, Symptoms, Sport, and Quality of Life). Radiological outcomes included lateral distal femoral angle, medial proximal tibial angle, and joint line convergence angle. RESULTS: Overall, 16 patients required conversion to TKA at a mean 86.75 ± 25.73 months (10-year survival rate, 87.2%). Only 2 patients in the HTO+ACI subgroup required a conversion to TKA (10-year survival rate, 94.3%). The complication rate for all patients was 8.8%. In both the HTO and HTO+ACI subgroups, VAS pain levels decreased and Lysholm scores increased significantly from pre- to postoperatively (P < .001). A higher preoperative Tegner score led to a significantly lower risk for conversion to TKA (P = .001), and a preoperative body mass index of ≥35 was associated with a significantly higher risk (P = .019), as was female sex (P = .046). Radiological parameters remained within physiological ranges. The postoperative joint line conversion angle did correlate with postoperative functional outcome but not with TKA conversion. CONCLUSION: Long-term results of HTO for medial compartment OA or cartilage defects with underlying varus deformity were good to excellent. In particular, patients who underwent HTO+ACI presented excellent long-term survival rates. HTO, therefore, delays or prevents TKA implantation, especially in young, active patients with medial compartment damage.

Individual Concepts in Foot Surgery: A Comparison of Xenogeneic and Autologous Bone Grafts Used in Adults for Lateral Calcaneus-Lengthening Osteotomy According to Evans.

BACKGROUND: Xenogeneic bone grafts, when compared to autologous grafts, are supposed to provide structural benefits without donor site morbidity. To date, there have been divergent results in the use of xenogeneic grafts in foot surgery, primarily in pediatric patient cohorts. The present study examines the incorporation and maintenance of the achieved correction using autologous and xenogeneic bone grafts in adult patients with a six-month follow-up period. MATERIAL/METHODS: In this retrospective study, 31 adult patients (43 feet in total) treated in our clinic by a lateral calcaneus-lengthening osteotomy, according to Evans, between 01/2006 and 12/2020 were included. The patients were assigned to study groups according to the use of xenogeneic or autologous bone grafts. The osseous incorporation following the criteria of Worth et al., correction maintenance by measuring the talo-navicular coverage angle (TNCA), the talo-first metatarsal angle (TFMA), the calcaneal pitch angle (PCA) and necessary revisions six months after surgery were extracted from the medical files retrospectively. Furthermore, the medical files were screened for the relevant comorbidities, nicotine abuse, BMI, sex and age. RESULTS: In total, 27 autogenous (iliac crest) and 16 xenogeneic bone grafts of bovine origin were used. The evaluation of the radiographs at follow-up demonstrated that there was a mean incorporation rate of 96.3% for the autologous grafts and 57% for the patients treated with xenogeneic grafts (p = 0.002). Compared to the autologous group, xenogeneic grafts did not increase the loss of hindfoot alignment in the postoperative course, regardless of being incorporated or not. ΔTNCA, ΔTFMA and ΔPCA displayed no significant differences in both groups (p = 0.45, p = 0.42 and p = 0.10). CONCLUSION: Despite a significantly lower incorporation rate, the use of xenogeneic grafts was not accompanied with a greater risk of hindfoot alignment loss in the first six months after surgery. Early revision after a postoperative course of six months should not be motivated solely by the radiographic picture of incomplete osseous integration.

Influence of surgical stabilization of clavicle fractures in multiply-injured patients with thoracic trauma.

Thoracic trauma has decisive influence on the outcome of multiply-injured patients and is often associated with clavicle fractures. The affected patients are prone to lung dysfunction and multiple organ failure. A multi-center, retrospective analysis of patient records documented in the TraumaRegister DGU was performed to assess the influence of surgical stabilization of clavicle fractures in patients with thoracic trauma. A total of 3,209 patients were included in the analysis. In 1362 patients (42%) the clavicle fracture was treated operatively after 7.1 ± 5.3 days. Surgically treated patients had a significant reduction in lung failure (p = 0.013, OR = 0.74), multiple organ failure (p = 0.001, OR = 0.64), intubation time (p = 0.004; -1.81 days) and length of hospital stay (p = 0.014; -1.51 days) compared to non-operative treatment. Moreover, surgical fixation of the clavicle within five days following hospital admission significantly reduced the rates of lung failure (p = 0.01, OR = 0.62), multiple organ failure (p = 0.01, OR = 0.59) and length of hospital stay (p = 0.01; -2.1 days). Based on our results, multiply-injured patients with thoracic trauma and concomitant clavicle fracture may benefit significantly from surgical stabilization of a clavicle fracture, especially when surgery is performed within the first five days after hospital admission.

Long-standing pubic-related groin pain in professional academy soccer players: a prospective cohort study on possible risk factors, rehabilitation and return to play.

BACKGROUND: Despite being a common overuse entity in youth soccer, scientific data on risk factors, rehabilitation and return to play for long-standing pubic-related groin pain is still rare. The current prospective cohort study aims to evaluate potential risk-factors, propose a criteria-based conservative rehabilitation protocol and assess return-to-play outcomes among professional youth soccer players suffering from long-standing pubic-related groin pain. METHODS: Male soccer players with long-standing (> 6 weeks) pubic-related groin pain from a professional soccer club's youth academy were analyzed for possible risk factors such as age, team (U12 - U23), younger/older age group within the team, position and preinjury Functional movement score. All injured players received a conservative, standardized, supervised, criteria-based, 6-level rehabilitation program. Outcome measures included time to return to play, recurrent groin pain in the follow-up period and clinical results at final follow-up two years after their return to play. RESULTS: A total of 14 out of 189 players developed long-standing pubic-related groin pain in the 2017/2018 season (incidence 7.4%). The average age of the players at the time of the injury was 16.1 ± 1.9 years. Risk factor analysis revealed a significant influence of the age group within the team (p = .007). Only players in the younger age group were affected by long-standing pubic-related groin pain, mainly in the first part of the season. Injured players successfully returned to play after an average period of 135.3 ± 83.9 days. Only one player experienced a recurrence of nonspecific symptoms (7.1%) within the follow-up period. The outcome at the 24-month follow-up was excellent for all 14 players. CONCLUSIONS: Long-standing pubic-related groin pain is an overuse entity with a markedly high prevalence in youth soccer players, resulting in a relevant loss of time in training and match play. In particular, the youngest players in each team are at an elevated risk. Applying a criteria-based rehabilitation protocol resulted in an excellent return-to-play rate, with a very low probability of recurrence. TRIAL REGISTRATION: The trial was retrospectively registered under DRKS00016510 in the German Clinical Trials Register on 19.04.2021.

The in vitro ToxTracker and Aneugen Clastogen Evaluation extension assay as a tool in the assessment of relative genotoxic potential of e-liquids and their aerosols.

In vitro (geno)toxicity assessment of electronic vapour products (EVPs), relative to conventional cigarette, currently uses assays, including the micronucleus and Ames tests. Whilst informative on induction of a finite endpoint and relative risk posed by test articles, such assays could benefit from mechanistic supplementation. The ToxTracker and Aneugen Clastogen Evaluation analysis can indicate the activation of reporters associated with (geno)toxicity, including DNA damage, oxidative stress, the p53-related stress response and protein damage. Here, we tested for the different effects of a selection of neat e-liquids, EVP aerosols and Kentucky reference 1R6F cigarette smoke samples in the ToxTracker assay. The assay was initially validated to assess whether a mixture of e-liquid base components, propylene glycol (PG) and vegetable glycerine (VG) had interfering effects within the system. This was achieved by spiking three positive controls into the system with neat PG/VG or phosphate-buffered saline bubbled (bPBS) PG/VG aerosol (nicotine and flavour free). PG/VG did not greatly affect responses induced by the compounds. Next, when compared to cigarette smoke samples, neat e-liquids and bPBS aerosols (tobacco flavour; 1.6% freebase nicotine, 1.6% nicotine salt or 0% nicotine) exhibited reduced and less complex responses. Tested up to a 10% concentration, EVP aerosol bPBS did not induce any ToxTracker reporters. Neat e-liquids, tested up to 1%, induced oxidative stress reporters, thought to be due to their effects on osmolarity in vitro. E-liquid nicotine content did not affect responses induced. Additionally, spiking nicotine alone only induced an oxidative stress response at a supraphysiological level. In conclusion, the ToxTracker assay is a quick, informative screen for genotoxic potential and mechanisms of a variety of (compositionally complex) samples, derived from cigarettes and EVPs. This assay has the potential for future application in the assessment battery for next-generation (smoking alternative) products, including EVPs.

Arthroscopic Bankart repair with an individualized capsular shift restores physiological capsular volume in patients with anterior shoulder instability.

PURPOSE: Capsular volume reduction in the context of anterior arthroscopic shoulder stabilization represents an important but uncontrolled parameter. The aim of this study was to analyse capsular volume reduction by arthroscopic Bankart repair with an individualized capsular shift in patients with and without ligamentous hyperlaxity compared to a control group. METHODS: In the context of a prospective controlled study, intraoperative capsular volume measurements were performed in 32 patients with anterior shoulder instability before and after arthroscopic Bankart repair with an individualized capsular shift. The results were compared to those of a control group of 50 patients without instability. Physiological shoulder joint volumes were calculated and correlated with biometric parameters (sex, age, height, weight and BMI). RESULTS: Patients with anterior shoulder instability showed a mean preinterventional capsular volume of 35.6 ± 10.6 mL, which was found to be significantly reduced to 19.3 ± 5.4 mL following arthroscopic Bankart repair with an individualized capsular shift (relative capsular volume reduction: 45.9 ± 21.9%; P < 0.01). Pre-interventional volumes were significantly greater in hyperlax than in non-hyperlax patients, while post-interventional volumes did not differ significantly. The average shoulder joint volume of the control group was 21.1 ± 7.0 mL, which was significantly correlated with sex, height and weight (P < 0.01). Postinterventional capsular volumes did not significantly differ from those of the controls (n.s.). CONCLUSION: Arthroscopic Bankart repair with an individualized capsular shift enabled the restoration of physiological capsular volume conditions in hyperlax and non-hyperlax patients with anterior shoulder instability. Current findings allow for individual adjustment and intraoperative control of capsular volume reduction to avoid over- or under correction of the shoulder joint volume. Future clinical studies should evaluate, whether individualized approaches to arthroscopic shoulder stabilization are associated with superior clinical outcome.

Reduced Recovery Capacity After Major Trauma in the Elderly: Results of a Prospective Multicenter Registry-Based Cohort Study.

AIMS: Considering the worldwide trend of an increased lifetime, geriatric trauma is moving into focus. Trauma is a leading cause of hospitalization, leading to disability and mortality. The purpose of this study was to compare the global health-related quality of life (HRQoL) of geriatric patients with adult patients after major trauma. METHODS: This multicenter prospective registry-based observational study compares HRQoL of patients aged ≥65 years who sustained major trauma (Injury Severity Score (ISS) ≥ 16) with patients <65 years of age within the trauma registry of the German Trauma Society (DGU). The global HRQoL was measured at 6, 12, and 24 months post trauma using the EQ-5D-3L score. RESULTS: We identified 405 patients meeting the inclusion criteria with a mean ISS of 25.6. Even though the geriatric patients group (≥65 years, n = 77) had a lower ISS (m = 24, SD = 8) than patients aged <65 years (n = 328), they reported more difficulties in each EQ dimension compared to patients <65 years. Contrary to patients < 65, the EQ-5D Index of the geriatric patients did not improve at 12 and 24 months after trauma. CONCLUSIONS: We found a limited HRQoL in both groups after major trauma. The group of patients ≥65 showed no improvement in HRQoL from 6 to 24 months after trauma.

The use of human induced pluripotent stem cells to screen for developmental toxicity potential indicates reduced potential for non-combusted products, when compared to cigarettes.

devTOX quickPredict (devTOX qP ) is a metabolomics biomarker-based assay that utilises human induced pluripotent stem (iPS) cells to screen for potential early stage embryonic developmental toxicity in vitro. Developmental toxicity potential is assessed based on the assay endpoint of the alteration in the ratio of key unrelated biomarkers, ornithine and cystine (o/c). This work aimed to compare the developmental toxicity potential of tobacco-containing and tobacco-free non-combustible nicotine products to cigarette smoke. Smoke and aerosol from test articles were produced using a Vitrocell VC10 smoke/aerosol exposure system and bubbled into phosphate buffered saline (bPBS). iPS cells were exposed to concentrations of up to 10% bPBS. Assay sensitivity was assessed through a spiking study with a known developmental toxicant, all-trans-retinoic acid (ATRA), in combination with cigarette smoke extract. The bPBS extracts of reference cigarettes (1R6F and 3R4F) and a heated tobacco product (HTP) were predicted to have the potential to induce developmental toxicity, in this screening assay. The bPBS concentration at which these extracts exceeded the developmental toxicity threshold was 0.6% (1R6F), 1.3% (3R4F), and 4.3% (HTP) added to the cell media. Effects from cigarette smoke and HTP aerosol were driven largely by cytotoxicity, with the cell viability and o/c ratio dose-response curves crossing the developmental toxicity thresholds at very similar concentrations of added bPBS. The hybrid product and all the electronic cigarette (e-cigarette) aerosols were not predicted to be potential early developmental toxicants, under the conditions of this screening assay.

In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota.

BACKGROUND: Strong interindividual differences in the microbial conversion of some dietary polyphenols have been reported. In-depth studies of trans-resveratrol metabolism by human gut microbiota, however, are lacking, and only one bacterial metabolite, namely dihydroresveratrol, has been described. OBJECTIVE: The aim of this study was to elucidate interindividual differences in trans-resveratrol metabolism by human gut microbiota and to identify bacterial strains involved. DESIGN: In the first part of the study, in vitro fermentation experiments were performed with feces samples from 7 healthy volunteers, and metabolite formation was measured by liquid chromatography-ultraviolet/visible (UV/Vis)-mass spectrometry (MS)/MS detection. Microbial diversities in 3 feces samples were analyzed by high-throughput pyrosequencing and quantitative real-time polymerase chain reaction. In addition, trans-resveratrol conversion experiments were conducted with selected fecal bacterial strains in pure culture. The second part of the study was a controlled intervention study with 12 healthy volunteers. After a washout period, all of the subjects received a one-time oral dose of 0.5 mg trans-resveratrol/kg body weight in the form of a grapevine-shoot supplement, and 24-h urine samples were analyzed by liquid chromatography-UV/Vis-MS/MS. RESULTS: Besides dihydroresveratrol, 2 previously unknown bacterial trans-resveratrol metabolites were identified in vitro and in vivo: 3,4'-dihydroxy-trans-stilbene and 3,4'-dihydroxybibenzyl (lunularin). Their formation, however, varied among the volunteers. Two strains, Slackia equolifaciens and Adlercreutzia equolifaciens, were identified as dihydroresveratrol producers. Gut bacteria able to produce dehydroxylated metabolites could, however, not be identified. CONCLUSIONS: trans-Resveratrol metabolism by human gut microbiota shows pronounced interindividual differences, which should be taken into account during investigation of health-related effects of this stilbene. This trial was registered at the German Clinical Trials Register as DRKS00004311, Universal Trial Number (WHO) UTN: U1111-1133-4621.